Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and ( þ )-borneol. Their EC 50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement.
Metoprolol and carvedilol are widely used in the treatment of hypertension, but no randomized comparison of their hemodynamic activity has been previously reported. Their comparative effects on heart rate, systemic blood pressure, and echocardiographically determined aortic and femoral artery blood flow were measured at rest and at 2 and 24 hours after the first dose of each drug, and again after 4 weeks of sustained monotherapy in 12 male and 12 female patients, aged 36-68 years with uncomplicated sustained hypertension according to a randomized single-blind protocol. Nine patients in each drug group achieved the target diastolic blood pressure of < 90 mmHg on the initial doses of each drug; this was achieved in the remainder following doubling of each dose. Neither drug occasioned withdrawal of any patient due to adverse reactions. Both drugs significantly reduced heart rate, although the reduction at 2 hours was significantly greater after metoprolol than after carvedilol. Both drugs reduced systolic pressure throughout the study; the reduction at 2 hours was significantly greater after carvedilol than after metoprolol. In contrast, the diastolic blood pressure was persistently reduced only by carvedilol. The cardiac output, determined as the aortic systolic blood flow, after carvedilol was not significantly different from pretreatment values throughout the study but was significantly reduced in the metoprolol-treated patients at each point of measurement. After metoprolol the systemic and femoral vascular resistances derived from conventional formulae were consistently and significantly increased over pretreatment values throughout the study and were significantly greater than in the carvedilol group at all measurement points. The hemodynamic differences between these two beta-blocking drugs may be explained by the additional vasodilator activity of carvedilol associated with its alpha 1-adrenoceptor blocking activity. The long-term clinical and prognostic implications of these pharmacodynamic differences between beta-adrenoceptor antagonists with and without additional vasodilator activity in the treatment of hypertensive patients remain to be determined.
Resting hemodynamics were measured before, at 2 and 24 h after the first dose, and after 4 weeks of monotherapy with either metoprolol or carvedilol in a randomized single-blind study. We analyzed results from 24 hypertensive patients (30-68 years of age) with adequate blood-pressure lowering on monotherapy. Acutely, both drugs lowered systolic blood pressure and heart rate. Whereas metoprolol reduced cardiac output and increased both systemic and femoral artery resistance, carvedilol did not alter cardiac output but led to reductions in the systemic and regional resistances. After 4 weeks of therapy, cardiac output remained reduced and vascular resistances increased in the metoprolol group, whereas in carvedilol patients cardiac output continued to be unchanged and the trend for vascular resistances to be decreased persisted. Acutely and chronically the differences in the hemodynamic effects of the two medications were statistically significant. The study results indicate that carvedilol's vasodilatory action is not subject to tolerance development. Chronic afterload reduction associated with the decrease in systemic vascular resistance may lead to additional savings in myocardial oxygen consumption, a beneficial feature particularly in those patients with concomitant ischemic heart disease. It may also have a favorable influence on concentric cardiac hypertrophy and changes in the walls of arteriolar resistance vessels.
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